Joseph A. Albanese, director of Analytical Strategy and Compliance at Janssen Research and Development, LLC

Joseph A. Albanese

silicon dioxide, also known as silica, is silicon oxide. Anti-caking agent, antifoam, viscosity controller, desiccant, beverage clarifier and medicine or vitamin excipient | Image Credit: ©RHJ -stock.adobe.com

 detailed a practical approach to establish specification equivalence for in-house harmonization to ensure multi-compendial compliance for excipients. Application of this approach allows a manufacturer to minimize testing for the material while remaining compliant with regulatory requirements in different regions of the world. This paper provides a technical assessment of compendial tests commonly found in the

United States Pharmacopeia–National Formulary (USP–NF)

, detailing differences between the methods and acceptance criteria, and the potential impact of these differences on multi-compendial compliance. Recommendations are also provided to facilitate a paper-based determination of specification equivalency. The assessments may be applied for in-house harmonization of drug substances and drug products, in addition to excipients.

Establishing Excipient Specifications–Considerations for Specific Tests

The following is a detailed assessment for many of the compendial tests typically used for excipients with a recommendation of which method may be most appropriate to select in an evaluation of specification equivalence. In general, minor differences between compendial methods are not expected to impact the fundamental pass/fail decision for a particular test and are not expected to necessitate the use of multiple compendial methods to assess multi-compendial compliance. Detailed considerations for the appropriate selection of specific test methods and acceptance criteria are provided below. The selection recommendations generally apply to a paper-based assessment of the methods, but may also include an evaluation of existing data, or a laboratory study. A monograph for a particular excipient may include tests in addition to these, and similar principles should be applied in evaluating any other compendial tests.The authors caution the readers that the conclusions suggested below are applicable to general tests/monographs as of June 2025, and users should confirm that there have been no subsequent updates to the pharmacopoeias.

Section 1. Tests/information included in monographs

Assessment: as stipulated in the General Notices of the 

, the appearance, characters, and/or description provided in a monograph for an excipient are not considered compendial requirements but are provided for information. These tests typically employ a simple visual assessment.

Selection: the specification may include a requirement for appearance that is appropriate for the material used, but the appearance is not considered a compendial requirement.

Appearance of solution (color and clarity/degree of opalescence)

are usually limit tests using standard solutions of color and opalescence for comparison to the sample (or sample solution) to evaluate conformance. Method differences may include sample preparation and solvent. The comparison is usually visual, although instrumental methods are also possible. By contrast, the tests in the 

are generally more qualitative, employing a simple visual assessment of color and clarity without comparison to specific reference solutions.

. method, with associated acceptance criteria, is considered superior due to the comparison to standards, and therefore is the method of choice to ensure compliance with similar tests in the 

 differences between compendial titration methods may include the use of visual or potentiometric endpoints, different titrants and indicators, and different concentrations of the sample, titrant, or indicator. In comparing compendial titration methods, these differences are not expected to have a significant impact on the analytical results or the pass/fail decision.

Selection: if the outcome of the method comparison is conclusive, standardizing to the 

 titration method will generally ensure compliance with 

 titration methods. The tightest acceptance criteria will be applied to ensure multi-compendial compliance.

Assessment: differences between chromatographic assay methods in the various compendia may include column packing, column dimensions, system temperatures, mobile phase, gradient or isocratic systems, injection volume, flow rate, detector type, detector wavelength, sample and standard concentrations and preparations, and system suitability requirements. Allowable variations for several of the chromatographic parameters are detailed in the corresponding 

 General Chapters. In considering chromatographic methods, many of these potential differences are not significant since the compendial methods have been validated for linearity, accuracy, repeatability, etc. and the results are expected to yield the same pass/fail decision.

Selection: if the outcome of the method comparison is conclusive, standardizing on a chromatographic assay method from the 

 chromatographic requirements. The tightest acceptance criteria will be selected to ensure multi-compendial compliance, with consideration given to whether the method has sufficient precision to allow application of the tighter limits.

Assessment: it is difficult to compare different assays where one test is performed by titration and another by chromatography. Titration procedures are generally more precise, but chromatographic methods are generally more selective. The acceptance criteria may also be different to reflect the precision of the particular method.

Selection: in many cases, it may be necessary to carry out analysis using both the chromatographic and titration assay method to ensure multi-compendial compliance for the excipient. There may be cases where the 

 titration assay method and acceptance criteria may provide assurance of conformance to the chromatographic assay methods in the 

. To help address potential issues with selectivity, the 

. titration method must be coupled with a chromatographic method for determination of impurities. There may also be cases where the 

 chromatographic assay method and acceptance criteria may provide assurance of conformance to the titration assay methods in the 

. Any such determination must be documented as part of the assessment carried out for the specific excipient.

Assessment: differences in compendial specifications for boiling point/distillation range may include the apparatus, rate of heating, and the acceptance criteria.

Selection: because there is minimal potential for the apparatus and heating to impact the result, the use of the 

method to determine the boiling point or distillation range will be used, with the tightest acceptance criteria applied.

Assessment: current good manufacturing practices (CGMPs) require that at least one specific identity test must be performed for all excipients. The underlying goal of identity testing is the confirmation, with an acceptable degree of assurance, of the material’s identity. Compendial monographs may include several different identity tests for the same material. Some of these tests are intended to identify the entire chemical or molecule (e.g., IR) while others are intended to identify a particular moiety (e.g., a selective chemical test for a specific counter ion). Specific identity tests are preferred to non-specific chemical tests. The 

. monographs may provide subdivisions entitled “First identification” and “Second identification”. The test or tests that constitute the “First identification” may be used for identification in all circumstances, as stated in the 

. General Notices. If the “First identification” tests are performed, the “Second identification” tests do not need to be performed.

“First identification” tests will be selected to establish the identity of the excipient. If the 

. monograph does not include divisions for “First identification” and “Second identification” tests, then all of the 

. identity tests will be included in the compendial release requirements, with the expectation that an excipient so identified would pass any other compendial identity tests. In the event that the 

 monograph includes an identity test for a specific characteristic of the excipient (e.g., a test for a particular counter ion or physical characteristic), which is not otherwise addressed by a comparable 

 test should also be performed to ensure compliance with the appropriate compendia. If there is no 

. monograph for the excipient, appropriate 

identity tests will be included, based on a similar principle.

Assessment: differences in IR identity methods typically involve sample preparation (Attenuated Total Reflectance [ATR], Potassium Bromide [KBr], mull, film, or solution) and are not considered significant when evaluating the fundamental properties of the chemical bonds through IR analysis. In most cases, the spectrum from a sample is compared to that of a reference standard or reference spectrum similarly prepared, which provides unequivocal information regarding the identity of the material. The specific wavelength ranges used for the test may also vary, but this is also not considered significant in making an appropriate identification determination.

Assessment: differences in UV identity methods may involve sample concentration, solvent, temperature, path length, and the particular wavelength used for the evaluation. Because most methods involve comparison to a reference standard or reference spectrum similarly prepared, these potential differences are not considered significant.

. UV method will generally ensure compliance with 

Assessment: different chromatographic identity procedures are capable of confirming the identity of the particular material. Differences between chromatographic method types (high-performance liquid chromatography [HPLC], gas chromatography [GC], or thin layer chromatography [TLC]) or differences between similar method types (see assay [chromatography] above) are not expected to have a significant impact on the ability of a particular method to establish the material's identity.

. chromatographic identity method will generally ensure compliance with 

Assessment: chemical identity methods may employ color change, precipitate formation, and/or solution formation based on a specific reaction of the excipient to provide assurance of the identity. Different tests may be necessary to ensure the identity for each moiety in a given excipient. Because an excipient may undergo a wide variety of reactions, there may be a large number of different chemical identity methods in compendial monographs for a material. These chemical methods are not typically specific to a particular excipient and therefore may not provide unequivocal identity. In addition to differences in the fundamental reactions utilized, these identification methods may also vary in the sample concentration and reagents used. Differences in chemical identity tests are not considered significant if the reactions are intended to evaluate the same chemical property of the material (such as presence of chloride). Multiple identification methods are usually unnecessary if one selective and specific method is available. Multiple tests may be necessary to demonstrate the identity of different moieties in the excipient.

chemical identity methods will be included in the compendial specification, if they are among the "First identification" tests. If the 

. chemical identity methods will be included in the compendial specification. No additional 

 chemical identity methods will typically be needed to ensure multi-compendial compliance.

Impurities–organic/related substances (chromatography)

Assessment: as with chromatographic assays, the differences between chromatographic impurities/related substances methods in the various compendia using HPLC may include column packing, column dimensions, system temperatures, mobile phase, gradient or isocratic systems, injection volume, flow rate, detector type, detector wavelength, sample and standard concentrations and preparations, and system suitability requirements. Another typical difference for impurities methods lies in the procedures used for calculating results (e.g., weight percent, volume percent, area percent, use of an internal standard, use of an external standard, or use of a diluted sample as standard). Allowable variations for several of the chromatographic parameters are detailed in the 

. General Chapter. In considering chromatographic methods, many of the potential differences are not significant because the individual methods are validated for linearity, accuracy, repeatability, etc. and the results should yield the same pass/fail decision. TLC may also be used as a suitable compendial method for control of impurities, although an HPLC method would generally be considered superior to TLC for quantitation, and this should be taken into account when selecting the test or tests required to ensure multi-compendial compliance for the excipient.

Selection: standardizing on a chromatographic method for impurities/related substances from the 

. will generally also ensure compliance with 

 requirements. The tightest acceptance criteria for each specified impurity should be selected to ensure multi-compendial compliance. The 

. General Monograph–Substances for Pharmaceutical Use and General Chapter 5.10 Control of Impurities in Substances for Pharmaceutical Use should also be considered when establishing the appropriate limits.

Assessment: There are a number of compendial tests which are intended to limit the amount of various inorganic impurities that may be present in excipients. These tests usually include wet chemical methods but may also employ instrumental methods. The test may be qualitative (i.e., pass/fail), semi-quantitative, or quantitative. These tests are not broadly applied to all excipients but are usually included in specific monographs as appropriate.

Examples of this type of test are aluminum, ammonium, arsenic, calcium, chlorides, iodides, iron, lead, magnesium, mercury, nickel, sodium, and sulfates. Wet chemical procedures generally rely on a chemical reaction to provide a visual change, such as color, turbidity, or formation of a precipitate, which enables a determination of the presence of the particular impurity at or below the acceptance criteria. Differences in compendial wet chemistry approaches for a specific inorganic impurity would typically involve different chemical reactions intended to detect the same impurity. Instrumental techniques may also be used for lower-level impurities or where greater sensitivity may be required. Instrumental methods are generally considered superior to wet chemical methods for determination and quantitation of inorganic impurities, as in the evaluation of an excipient for elemental impurities. Other than as listed in specific excipient monographs, a test for an inorganic impurity would only be included if the elemental impurities assessment determines there is a need to employ a control strategy for a specific inorganic impurity in the particular excipient.

Selection: if the outcome of the method comparison is conclusive, standardizing on a wet chemical procedure from the 

. for these types of inorganic impurities will generally also ensure compliance with 

 wet chemistry requirements for the particular impurity. An instrumental compendial method is generally superior to a wet chemical method and this should be taken into account when selecting the test or tests required to ensure multi-compendial compliance for the excipient. Standardizing on an instrumental procedure from the 

. for inorganic impurities will generally also ensure compliance with 

 wet chemical or instrumental requirements. The tightest acceptance criteria for the particular impurity should be selected to ensure multi-compendial compliance. Consideration should also be given to the superior, International Council for Harmonisation (ICH)/ Pharmaco-poeial Discussion Group (PDG) risk-based approach for control of elemental impurities (including appropriate test methods and acceptance criteria).

Assessment: Differences in LOD methods typically involve sample size, temperature, time, vacuum, and desiccants in the procedure for drying. The differences may have an impact on the result obtained and should be considered in selecting the method to be used. If the method specifies that the test is performed until constant weight is achieved, the differences in the methods are not expected to impact the final result, and the identical pass/fail decision should be reached.

Selection: If the outcome of the method comparison is conclusive, standardizing on the 

. method for LOD will generally ensure compliance with 

requirements. The tightest acceptance criteria should be applied to ensure multi-compendial compliance. In establishing the acceptance criteria, the impact of time and temperature on the result should be considered (i.e., the longer the time and the higher the temperature, the higher the expected LOD result) to ensure the tightest acceptance criteria are applied.

Assessment: Differences in compendial methods for these tests may include the apparatus, heating rate and the acceptance criteria.

Selection: Because there is minimal potential for the apparatus and heating to impact the result, the use of the 

. method to determine the melting point or range will be used, with the tightest criteria applied.

Microbiological tests (microbial limits, bacterial endotoxins, sterility)

Assessment: The microbiological tests in the 

 have been harmonized by PDG and assessed by ICH Q4B. Based on this assessment, the tests in the individual compendia are equivalent.

Selection: Typically, the microbiological procedures from the 

 will be selected with appropriate consideration of sample qualification requirements.

Assessment: Differences in pH methods typically include instrumentation, indicators, sample concentration, and measurement temperature. These differences may impact the result obtained and should be considered when selecting the method to use. The impact of sample concentration on the result may be considered in terms of the Henderson-Hasselbalch equation. Acidity or alkalinity of a sample is determined by assessing the occurrence or absence of a color change upon adding an acidic or basic reagent in the presence of an appropriate indicator. Differences in acidity or alkalinity tests may include sample concentration, solvent, titrant, and/or indicator.

Selection: Tests for pH and acidity/alkalinity evaluate the same fundamental attribute for the material related to its inherent acidic or basic functional groups, or those of residual materials present along with the excipient itself. If the outcome of the method comparison is conclusive, standardizing on the 

 method for pH or acidity/ alkalinity will generally ensure compliance with the corresponding 

 methods. For pH, the tightest acceptance criteria may generally be applied to ensure multi-compendial compliance. For acidity/alkalinity, the acceptance criteria associated with the selected method should be applied.

Assessment: The primary difference in refractive index methods for liquid excipients is the measurement temperature. The expected trend for the effect of temperature on the result is difficult to predict. Despite temperature differences in methods, the refractive index result, as a fundamental physical property, is expected to comply with the corresponding, appropriately established acceptance criteria.

 method for refractive index will generally ensure compliance with 

 requirements. The specific acceptance criteria associated with the selected method should be used.

Assessment: Differences in specific gravity/density methods typically involve sample preparation (neat liquid or solution), solvent, and the measurement temperature. The general trends expected are that the higher the sample concentration, the higher the result, while the higher the temperature for the test, the lower the specific gravity/density result. Despite differences in methods, the specific gravity/density result, as a fundamental physical property, is expected to comply with the corresponding, appropriately established acceptance criteria.

method for specific gravity/density will generally also ensure compliance with 

 requirements. The acceptance criteria associated with the selected method should be applied.

Assessment: Differences in specific rotation/optical rotation methods typically involve sample preparation, solvent, measurement temperature, path length, and detection wavelength. The general trends expected are that the higher the concentration and the longer the path length for the test, the higher the expected rotation result. Despite differences in methods, the specific rotation/optical rotation result, as a fundamental physical property, is expected to comply with the corresponding, appropriately established acceptance criteria.

 method for specific rotation/optical rotation will generally also ensure compliance with 

requirements. The acceptance criteria associated with the selected method should be applied.

Assessment: The tests for sulphated ash/residue on ignition in the 

. method for sulphated ash will also ensure compliance with 

 requirements. The tightest acceptance criteria should be applied to ensure multi-compendial compliance.

Assessment: Differences in total ash/LOI methods typically involve sample size, ignition temperature, and ignition time used in the procedure. The 

 carry out the test to constant weight, which should provide the highest loss on ignition result (i.e., a more stringent assessment).

 method for total ash/LOI will generally ensure compliance with 

Assessment: Differences in rotational viscometer (e.g., Brookfield) methods typically involve sample concentration, measurement temperature, spindle, speed, and instrumentation. Use of capillary viscometers (e.g., Ubbelohde-Type and Ostwald-Type) is also very common in excipient monographs and methods may differ in sample concentration and temperature. The expected trends are that the higher the sample concentration, the higher the resulting viscosity, and the higher the temperature, the lower the resulting viscosity. It is difficult to compare rotational and capillary viscosity methods. Despite differences in methods, the viscosity result, as a fundamental physical property, is expected to comply with the corresponding, appropriately established acceptance criteria.

 method for rotational or capillary viscosity will generally ensure compliance with the corresponding 

 methods. The acceptance criteria associated with the selected method should be applied.

Assessment: Differences in water determination using titrimetric methods include sample amount, solvent, titrant, titrant concentration, and end-point determination (potentiometric or coulometric). These differences are not expected to have a substantial impact on the result obtained using a suitably qualified and calibrated instrument that is appropriate for the expected amount of water in the sample. For determination of low levels of water, a coulometric/micro procedure is preferred.

 method for water will generally ensure compliance with 

 requirements. The tightest acceptance criteria should be applied to ensure multi-compendial compliance. Appropriate consideration for the method, sample amount, and acceptance criteria should be given for low-level water determinations.

Waxes, fats, and fixed oils—typical properties (e.g., acid value, hydroxyl value, iodine value, saponification value)

Assessment: Differences in the wet chemical procedures used to determine particular properties of waxes, fats, and fixed oils may include the sample preparation, reagents, indicators, titrants, and test conditions. However, for a particular procedure, differences in the compendial methods would not typically be expected to produce a different result. The acceptance criteria may be different in the different compendial monographs.

 method for a particular procedure, (e.g., saponification value) will generally ensure compliance with the 

 requirements for the same procedure (e.g., saponification value). The tightest acceptance criteria should be applied to ensure multi-compendial compliance.

Section 2. Additional tests to be considered

Assessment: Residual solvents in pharmaceuticals are defined in the International Council for Harmonisation (ICH) Q3C guideline (2) as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The guideline recommends acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The approach to limit residual solvents as specified in the ICH guideline is also included in the 

 general notices, general monographs, and general chapters. A manufacturer needs to demonstrate that the levels of residual solvents comply with the limits established in ICH Q3C, and that solvent levels are maintained using an appropriate control strategy that encompasses the drug product and all of its components. As such, residual solvents in excipients must be controlled to comply with the ICH and pharmacopoeia requirements.

Selection: The harmonized approach to residual solvent control listed in the pharmacopoeias should be used for an excipient, including the appropriate test method and acceptance criteria.

Assessment: The ICH Q3D guideline (3) presents a process to assess and control elemental impurities in the drug product using the principles of risk management as described in ICH Q9 (4). Although focused on the drug product, the guideline recognizes that, among other potential contributors, elemental impurities may be present in the excipients used in the preparation of the product and must therefore be considered in the overall risk assessment. The ICH Q3D guideline is also being incorporated into the pharmacopoeias, and consideration of elemental impurities is required by the pharmacopoeial general notices. The harmonized general chapter by PDG is being implemented, with the 

 being the last to make it official in July 2026 (5). For pharmaceutical manufacturers, adoption of the harmonized approach to elemental impurities is recommended for acceptance into major markets. Whenever the elemental impurities risk assessment for a drug product requires testing a particular excipient for a specific element, or if a test for a specific metal impurity is listed in the excipient monograph, the test method from the pharmacopoeia should be used whenever possible and appropriate.

Selection: The test method recommendations listed in the harmonized chapter “Elemental Impurities” as published in the pharmacopoeias should be used in the determination of elemental impurities, as needed for an excipient. Acceptance criteria listed in the harmonized pharmacopoeia chapter for a specific elemental impurity should be applied to the excipient being tested, ensuring the limit is appropriate for the overall drug product risk assessment.

Assessment: The test for heavy metals is a wet-chemistry limit test that has long been included in pharmacopoeia monographs. The test is intended to detect the presence of metal impurities that form insoluble precipitates with sulfide ion. The metals that respond to this test typically include lead, mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper, and molybdenum. Long-standing questions about the test’s usefulness to accurately detect these metals contributed to the introduction of the ICH/PDG risk-based assessment of elemental impurities that are likely to be present. (See above.)

Selection: It is possible that a test for heavy metals may still be listed in the pharmacopoeia monograph for a particular excipient, especially in national pharmacopoeias that are not currently part of PDG; although, this should become increasingly rare. Applying the superior, risk-based approach for control of elemental impurities (including appropriate test methods and acceptance criteria) and testing particular excipients to limit specific metals that may be present, should in all cases be considered an acceptable alternative to the wet-chemistry test for heavy metals.

 have introduced controls for a risk-based N-nitrosamine evaluation for drug substances and excipients. Many N-nitrosamines are classified as probable human carcinogens and regulators are taking action to ensure these impurities are minimized or eliminated from substances and final drug products. The requirements for control of N-nitrosamines are being captured in pharmacopoeial general chapters. 

. General Monograph 2034 Substances for Pharmaceutical Use includes a requirement to establish a control strategy for N-nitrosamines. The control strategy is listed in 

 General Chapter <1469> Nitrosamine Impurities provides recommendations regarding: a) the establishment of controls of nitrosamine levels in order to ensure their elimination or reduction; and b) analytical procedure performance characteristics for procedures used to monitor nitrosamine levels. Many health authorities have also issued guidance documents that are applicable for the evaluation of nitrosamine levels.

Selection: Manufacturers should consider whether control of nitrosamines is necessary for the excipients used in their drug products, including the selection of appropriate test methods and acceptance criteria. Manufacturers should also remain vigilant to current nitrosamine requirements, given the dynamic state of regulatory expectations and the lack of harmonization to date among the pharmacopoeias.

Tests for ethylene glycol (EG), diethylene glycol (DEG) and triethylene glycol (TEG)

 have all introduced testing to control EG, DEG, or TEG in several high-risk monographs in response to the public health concerns posed by the potential presence of these contaminants in medicinal products (6-11). Regulatory agencies around the world are also issuing guidance for control of these toxic impurities. To date, the pharmacopoeia and regulatory approaches have not been harmonized.

Selection: Manufacturers need to be aware of these monograph changes as well as the regulatory guidance documents for controlling EG, DEG, and TEG that are being issued directly by global health authorities to combat adulteration of drug products. For example, FDA has issued a guidance document (12) that targets several high-risk excipients and requires that each drum of the material be sampled and tested to comply. Companies will need to execute testing required in individual monographs to ensure compliance with the testing for these contaminants. Given the intense focus of pharmacopoeias and regulators on this area, companies should ensure compliance with country or regional requirements as they continue to evolve.

This article has provided a detailed assessment of compendial tests commonly found in the pharmacopoeias, highlighting differences between the methods and acceptance criteria, and the potential impact of these differences on multi-compendial compliance. This information serves to supplement the previous article (1), which detailed a practical approach for establishing specification equivalence for in-house harmonization to ensure multi-compendial compliance for excipients. The first two articles (13,14) in this series introduced the concepts and provided a streamlined, step-by-step process for establishing specification equivalence. Taken together, these four articles provide the opportunity to gain efficiency by minimizing redundant testing for drug products and their ingredients, while also enabling flexibility in filing strategies.

Articles

This article provides a comprehensive technical assessment of compendial tests from the European Pharmacopoeia, United States Pharmacopeia–National Formulary, and Japanese Pharmacopoeia, focusing on differences in methods and acceptance criteria. It offers recommendations for selecting appropriate methods to ensure multi-compendial compliance, emphasizing the importance of standardizing on Ph. Eur. methods for various tests. The article also discusses additional considerations for residual solvents, elemental impurities, heavy metals, nitrosamines, and specific contaminants like ethylene glycol. This guidance aims to streamline testing processes and enhance regulatory compliance.

This paper provides a technical assessment of compendial tests commonly found in the European Pharmacopoeia, the United States Pharmacopeia–National Formulary, and the Japanese Pharmacopoeia, detailing differences between the methods and acceptance criteria, and the potential impact of these differences on multi-compendial compliance.

Multi-Compendial Compliance for Pharmaceutical Excipients–Part 2: A Detailed Assessment for Specification Equivalence

Lactose Monohydrate, is the sugar present in milk and its derivatives, it is a diluent excipient commonly used in the development of formulations to give volume to the pharmaceutical form | Image Credit: © RHJ -stock.adobe.com

In an earlier series of articles by Wiggins and Albanese addressing the challenges of pharmacopoeia compliance, consideration was given to the global regulatory expectations and requirements, with guidance provided on how to address the potential misalignment of compendial monographs and drug product registrations (1). A subsequent article in that series provided a case study detailing the specific challenges for excipients (2). That article listed several strategies to ensure multi-compendial compliance for excipients and included a brief discussion on internal or in-house harmonization. Previous articles in this current series have introduced the concepts and provided the tools for establishing specification equivalence (3,4). The present article details a practical application of specification equivalence to excipients testing to achieve in-house harmonization.

Excipients are present in essentially every pharmaceutical product currently approved and marketed around the world. For most of these drug products, excipients comprise the vast majority of the dosage form content. Oftentimes, a small number of different excipients are used in a wide variety of products in a company’s portfolio. For example, many solid oral dosage forms combine the active drug substance with common excipients, including lactose, starch, microcrystalline cellulose, magnesium stearate, and titanium dioxide, among other ingredients. Pharmacopoeia monographs exist for most common excipients, and regulatory agencies require conformance with these monograph requirements.

Compliance with the quality requirements for excipients as published by pharmacopoeias around the world is a significant challenge in global registration and distribution of medicinal products (pharmaceuticals, biologics, and vaccines). Establishing appropriate specifications through in-house harmonization can help ensure compliance with excipient monographs in multiple pharmacopoeias to provide meaningful benefits. These include minimizing the testing needed to ensure compliance with pharmacopoeia requirements and health authority expectations while also enabling flexibility in filing strategies. The approach is based on the principles of specification equivalence presented in the earlier articles in this series and addresses regulatory expectations and requirements at a global level, while reducing redundant testing of multi-compendial excipients by a bio/pharmaceutical company.

As indicated in the General Notices of the 

United States Pharmacopeia–National Formulary

), compendial compliance can be summarized as follows: an excipient would pass if tested by the compendial methods; however, alternative methods can be used to demonstrate conformance. A similar statement is included in the General Notices of the 

) and applies not only to materials listed in the 

), whose General Notices refer to those in the 

. General Notices contains an additional expectation that the use of alternative methods requires agreement of the competent regulatory authority, stating in the event of doubt or dispute, the analytical procedures of the applicable pharmacopoeia are alone authoritative in determining compliance (5). The determination of specification equivalence as detailed in previous articles by the authors established that acceptance criteria must also be considered when ensuring overall compliance with quality requirements. Once appropriately harmonized specifications have been established for a given excipient, ongoing compliance must be maintained when compendial revisions occur, with appropriate change control documented through the company’s quality management system.

Establishing Excipient Specifications–Consideration of the Pharmacopoeias

The goal of determining specification equivalence for excipients is to ensure compliance with the requirements contained in all applicable pharmacopoeias for that material. Still, common sense also comes into play when determining whether and when to evaluate specification equivalence for the excipients in a drug product. For example, if a product is only approved in one country, the excipients used in that product only need to meet the pharmacopoeia requirements in that country. If a product is approved in multiple countries but a specific excipient batch will be used in product batches going only to one country, then compliance with the pharmacopoeia in that single country is necessary for that excipient batch. However, most excipients and specific batches may be used in multiple products for distribution in many countries, and it may be beneficial for a company to follow a risk-based approach to testing by performing in-house harmonization of the multiple pharmacopoeia monographs, through specification equivalence, to reduce redundant testing.

In considering the compendial scope for the equivalence evaluation, it is useful to remember there are currently as many as 40 pharmacopoeias that may be applicable around the world (6). It is also helpful to consider the suggestion that three pharmacopoeias in particular—

)—may be considered “global pharmacopoeias”, meaning they are acceptable to regulators well beyond the boundaries of the country or region in which they are established (7). However, other applicable national pharmacopoeias must be considered for products that are approved and marketed in many other major markets.

Although this article focuses on establishing specification equivalence through in-house harmonization of excipients for compliance to requirements in the 

—the original members of the Pharmacopoeial Discussion Group (PDG)—the approach may be extended to other national pharmacopoeias as needed, including the 

. Similarly, the approach can be extended to excipients listed in the 

 is required to publish all the same monographs as contained in the 

., according to the European Pharmacopoeia Convention to which the 

 was one of the initial signatories. There are only a handful of excipients that are listed in the 

 alone and otherwise not included in the 

Establishing Excipient Specifications–Approach

The International Council for Harmonisation (ICH) Q6A and Q6B guidelines define a specification as a list of tests, references to analytical procedures, and appropriate acceptance criteria used to demonstrate that a material is acceptable for its intended use (8,9). The specification for an excipient establishes the identity, purity, and quality of the material. For a given excipient, the specifications in the compendial monographs of various pharmacopoeias are often generally consistent in terms of the types of tests required for conformance (e.g., assay, impurities, pH, loss on drying, etc.). The methods in the various compendia are sometimes identical but may have differences that generally do not impact the ability to assess a particular quality attribute for the material. The acceptance criteria in the various compendia for the same test, however, may be different; nevertheless, compliance with all appropriate compendial acceptance criteria is required.

The process for selecting a particular method and acceptance criteria to ensure compliance with multi-compendial requirements calls for a thorough, scientific evaluation of the different monographs and general chapters in each of the pharmacopoeias, with appropriate documentation of the decisions reached. The detailed technical assessment of the monograph requirements is intended to justify the final in-house harmonized specification. In comparing compendial tests, it is understood that the methods have been validated and/or demonstrated to be suitable for the analysis of the particular material to which the test is applied. The compendial acceptance criteria are similarly considered appropriate for ensuring the purity and quality of the excipient. Standardizing on the 

. method, when appropriate, addresses the expectation in Europe that the use of alternative methods requires agreement of the competent regulatory authority.

. A comparison of two or more compendial methods for a particular quality attribute may enable the use of a single method to ensure compliance, thereby minimizing redundant testing. Differences between the methods are evaluated to establish their suitability to assure the identity, purity, and quality of the excipient. The selected method must provide the same result, to the extent this is practical, and the same accept/reject decision must be reached for the material tested. The recommendations generally apply to a paper-based assessment of the methods, but may also include an evaluation of existing data, or a laboratory study. The following terms are used to define the possible types of evaluation (See also 

, reproduced from an earlier article [4]):

Paper-based method assessment–A method review (paper evaluation only) to determine whether two (or more) methods are equivalent

Existing data comparison–An analytical evaluation of historical test data to determine whether two (or more) methods are equivalent

Assessment of data from laboratory studies–An analytical laboratory evaluation carried out to determine whether two (or more) methods are equivalent.

Figure 1. Specification equivalency assessment process flow. Figure courtesy of authors.

The following terms are used to define the outcome of method evaluation:

Equivalent–Based on an equivalency study, two (or more) methods that provide the same analytical results and the same accept/reject decision is reached

Not equivalent–Two (or more) methods determined to be non-equivalent based on a paper-based method assessment, comparison of existing data, and/or assessment of data from laboratory studies

Superior–A method that is determined to provide advantages over another method, in terms of increased accuracy, precision, sensitivity, and/or selectivity, etc., based on a paper-based method assessment, comparison of existing data, and/or assessment of data from laboratory studies. Note that appropriate sensitivity should be used when an evaluation concludes a method in one pharmacopoeia is superior to a method in another pharmacopoeia. The technical justification should be written with the understanding that the document may be reviewed during an inspection by the regulatory agency from the country with the inferior pharmacopoeia method. It may also be appropriate to consider submitting a revision request to that pharmacopoeia to adopt the superior method.

. Some analytical methods have undergone harmonization by PDG and may have been subjected to further evaluation of interchangeability by the regulatory agencies through the ICH Q4B process (10). This harmonization process (PDG and/or Q4B) enables the use of any of the compendial methods to ensure multi-compendial compliance. PDG has also harmonized several excipient monographs in the 

, and this outcome may be used as justification to perform testing according to one pharmacopoeia to meet the requirements of all three. For those monographs where PDG has harmonized by attribute, meaning some of the specific tests have not been aligned across the pharmacopoeias, the approach detailed in this article may be applied to those non-harmonized attributes, to further reduce redundant testing. Additional detailed information on harmonization approaches and progress may be found in previously published articles that were focused on pharmacopoeia compliance (11,12).

To achieve multi-compendial compliance, the tightest acceptance criteria will generally be applied. However, it is recognized that analytical methods and acceptance criteria are necessarily interrelated. In cases where the underlying chemical or analytical principles are essentially the same, the tighter limits from one of the compendia may be applied to ensure compliance with all of the compendial requirements. For acceptance criteria with overlapping ranges, the appropriate upper and lower limits may be used to create the tightest range. In cases where the test result is affected by dependent variables (e.g., temperature or concentration), the association of the method and acceptance criteria will be maintained.

Establishing excipient specifications–Recommendations

The following principles may be generally applied in establishing appropriate specifications to ensure multi-compendial compliance for excipients. Consideration is given to the list of tests, the analytical procedures for these tests, and the associated acceptance criteria for a given excipient.

, as applicable) are included in the specification for the excipient. However, not all of the methods associated with these tests necessarily need to be performed, as detailed below, and in 

Figure 2. Figure courtesy of the authors.

 Two or more compendial methods for a particular test or quality attribute may be compared, and redundant testing minimized through the following selection process for the excipient:

 method is necessary if it is determined to be equivalent or superior to the 

 method(s), based on a paper-based method assessment.

If the outcome of the paper-based method comparison is not conclusive, then assessment of existing data or data generated in a laboratory study may be performed to assist in the evaluation. If the assessment is still not conclusive, and in the absence of additional information, the compared methods should be considered not equivalent.

 method is selected if it is determined to be equivalent or superior to the 

Additional methods for tests appearing only in the 

Where two or more compendial methods for a particular quality attribute for a given excipient have been compared, and a single method has been selected, the appropriate acceptance criteria are selected according to the following process:

Generally, the tightest/most stringent acceptance criteria are selected. In some instances, it may be necessary to modify the selected method (e.g., sample and/or standard concentration) to allow assessment of compliance with the tightest acceptance criteria.

Generally, for acceptance criteria ranges, the limits from different compendia may be combined to provide the tightest/most stringent acceptance criteria.

In cases where the acceptance criteria are inherently linked to the methodology (e.g., temperature- or concentration-dependent tests), the association between method and acceptance criteria will be maintained and a single method may be utilized, provided the acceptance criteria shift is consistent with chemical and/or physical principles for the material and method.

Where compendial methods have not been compared, have been determined to be not equivalent, or are unique, the acceptance criteria associated with the method are selected.

A detailed listing of compendial tests commonly found in the 

, an assessment of differences between the methods and acceptance criteria, and the potential impact of these differences on multi-compendial compliance is provided in the next paper in this series (13).The details for the specific methods are intended to provide guidance in the assessment of the different tests in compendial monographs and provide selection recommendations to ensure multi-compendial compliance. These detailed method assessments may be applied to tests for drug substances and drug products, in addition to excipients.

Extending excipient specification equivalence to additional pharmacopoeias–example

This article has focused on specification equivalence to achieve in-house harmonization for excipients listed in the 

. The principles, however, may be extended to include other pharmacopoeia requirements.

For example, sodium hydroxide may be used as an excipient in a drug product distributed to the European Union, United States, and Chinese markets. Therefore, sodium hydroxide will have to comply with the pharmacopoeial monographs (current as of June 2025) in the 

 captures the methods and acceptance criteria for the sodium hydroxide monographs in each of the pharmacopoeia for the reader's understanding. To minimize the redundant testing needed to comply with all the monographs, a specification equivalence report may be generated evaluating each quality attribute. Some of the test attributes are straightforward to determine but others are not. For the sake of brevity, this article will focus on only four attributes: pH; chlorides; potassium; and the test for aluminum and iron:

For the pH test, each monograph requires a dilution of the sodium hydroxide, and the resultant solution pH is measured. The same acceptance criteria for all three monographs is “not less than 11”. Following the recommendation in this article, use of the test method listed in the 

. may be used to ensure compliance with all three pharmacopoeia monographs.

For the chlorides test, which is only present in the 

 tests are chemical reactions where the test sample is compared to the standard solution to ensure the same or less opalescence. The limit of the 

 monograph limit is 50 ppm. In this case, some lab work needs to be performed to determine if the 

 method can demonstrate the change at 50 ppm. If it does, the 

. method should be run. If it does not, then the methods are not equivalent, and each method should be run.

 use of atomic absorption spectroscopy is superior to the 

 chemical reaction test. Also, the company would need to determine the potassium concentration that produces opalescence in the 

 limit of 0.5% (5000 ppm) is appropriate.

The test for aluminum and iron appears only in the 

 monograph. Specification equivalency is not applicable for this attribute so the 

Achieving multi-compendial compliance for excipients in pharmaceuticals is crucial for global distribution. In-house harmonization of excipient specifications, based on specification equivalence, can streamline compliance with various pharmacopoeias, reducing redundant testing. This involves evaluating and selecting appropriate methods and acceptance criteria from major pharmacopoeias like Ph. Eur., USP–NF, and JP. The process includes method evaluation, harmonization, and acceptance criteria assessment. Extending these principles to other pharmacopoeias can further enhance compliance. This approach ensures excipients meet global regulatory expectations while optimizing testing and filing strategies.

The authors detail a practical application of specification equivalence to excipients testing to achieve in-house harmonization.